tbuckley/cabot-search huggingface dataset:
Genomic characterization of the GATA3 mutational landscape in breast cancer.
Authors: Jason A Mouabbi, Funda Meric-Bernstam, Polina Turova, Konstantin Chernyshov, Vladimir Kushnarev, Nikita Kotlov, Jessica H. Brown, Patrick Clayton, Krystle Nomie, Nathan Fowler, Debu Tripathy, Senthil Damodaran
Journal: Journal of Clinical Oncology (2023)

1039 Background: GATA3 expression is broadly used as a biomarker for diagnosing cancer of breast origin and its expression is strongly associated with estrogen receptor (ER)-positive luminal phenotype. Although GATA3 mutations are observed in 12-18% of breast cancers (BC), they are poorly characterized. Recently, the pharmacological inhibition of MDM2 has been shown to significantly impair tumor growth in GATA3-deficient models in vitro, in vivo, and patient-derived xenograft harboring GATA3 somatic mutations. Therefore, given the potential targetability of GATA3-mutated BC cells, it is important to better understand and characterize the mutational landscape of GATA3 to help guide future prospective clinical studies. Methods: We accessed a cohort of BC samples profiled genomically and transcriptomically from two open-source datasets: TCGA (n=961) and METABRIC (n=1866). We used the chi-squared test to analyze the frequency of GATA3 mutations across PAM50 subtypes (Basal, HER2, Luminal A, Luminal B, Normal-like) and histological BC subtypes (invasive ductal carcinoma [IDC] and invasive lobular carcinoma [ILC]). Mutations affecting other genes in the GATA3-mutated samples and the GATA3 wild-type (WT) samples were compared using the chi-squared test. We analyzed the mutational landscape of the GATA3 gene and correlated different sites of mutations with GATA3 expression, MDM2 amplification, other co-occurring mutations, and clinical behavior. GATA3 expression levels were compared using the Mann-Whitney test. Results: Of the analyzed 2,827 BC samples, GATA3 mutations were unevenly distributed in the five PAM50 subtypes, as Luminal A and B subtypes had the highest frequency (16% and 17%, respectively) and the basal subtype had no observed GATA3 mutations (p &lt;0.0001). Further analysis showed that GATA3 mutations were more common in luminal IDC than ILC (17% vs 8.7%; p &lt;0.0001). While mutations in CBFB, AKT1, TBX3 and ARID1A were more frequently co-occurring with GATA3 mutations, mutations in TP53, CDH1 and PIK3CA were mutually exclusive with GATA3 mutations (adjusted p &lt;0.0001 for all genes). Analysis of the GATA3 mutational landscape identified two types of mutations in GATA3: a group of truncating mutations occurring at the end of the GATA3 gene (after the 307 position including the splice site at 308) and a group occurring before the 307 position. The first group was associated with increased GATA3 expression, MDM2 amplification, and was mutually exclusive with TP53 mutations. The second group had little to no effect on GATA3 expression and behaved similarly to GATA3 WT. Conclusions: A subtype of GATA3 mutations are mutually exclusive with TP53 mutations and are associated with increased MDM2 amplification, making them an ideal target for clinical trials involving MDM2 inhibitors.
Overall breast cancer survival and prognostic factors.
Authors: Hanane Benzebda, Soumeyya Bezzar Ghomari
Journal: Journal of Clinical Oncology (2023)

e12525 Background: Breast cancer is a frequent and heterogeneous disease where several clinical, histological and molecular factors determine its prognosis. Our objective is to estimate the prognostic factors influencing overall survival (OS) in patients with breast cancer. Methods: We conducted our first descriptive and analytical single-center study with a retrospective collection of data on files from the Medical Oncology department in University Hospital Center Tlemcen, including patients who died in 2020-2021 and were treated for breast cancer in order to estimate overall survival and determine prognostic factors. The study of survival was carried out by the Kaplan Meier method, and the comparison between the different classes of a variable was carried out by the log rank test. The study of prognostic factors associated with survival was carried out using the Cox model. Results: One hundred twenty-four patients were included. The average age was 50 years [30-87]. The median overall survival in our study, was 48 months [37-58].Seventy-four patients (57.9%) were diagnosed at a localized stage, 50 (40.3%) at a metastatic stage (p = 0.0001; CI: 95%). More than half of the patients, were under 50 years old, 36 were between 50 and 65 years old, and 22 were ≥ 65 years old (p = 0.8; CI: 95%). Forty-seven patients (37.6%) had a tumor located in the right breast, 67 (53.6%) in the left breast and 7 patients (5.6%) had bilateral breast cancer (p = 0.8). Seventy-nine patients (63.7%) underwent a radical mastectomy type Patey, 3 (2.4%) conservative surgery, 9 (7.3%)palliative mastectomy and 33 (26.6%) were not operated (p = 0.02; CI: 95%). The histological type was non-specific infiltrating ductal carcinoma in 93 patients (75.6%) and invasive lobular carcinoma in 14 patients(11.4%) (p = 0.04). Sixty-seven patients (53.6%) had a grade 2 and 38(30.4%) grade 3 (p = 0.08). Tumor size was T0 (0.9%), T1 (8.4%), T2 (44.9%), T3 (13.1%), T4 (32.7%) (p = 0.02). Lymph node involvement was N0 (19.4%), N1 (28.7%), N2 (35.2%), N3 (16.7%) (p = 0.054). In immunohistochemistry; 22 (45.8%) patients had a Ki67 &gt; 20% and 26 patients (54.2%) had a Ki67 ≤ 20% with (p = 0.22). Twenty patients (16%) had a positive HER2 (p = 0.7). Seventy-one patients (61.2%) had positive hormone receptors with a median OS of 57 months [34.79] (p = 0.0001). High expression of estrogen hormone receptors (≥ 50%) had no impact on overall survival (p = 0.06) while high expression of progesterone hormone receptors was associated with better overall survival (p = 0.01). Conclusions: Breast cancer is a frequent and heterogeneous disease with several factors influencing its prognosis. The initial stage of the disease, a radical surgery, the infiltrating ductal histological type, the tumor size and the level of expression of the progesterone receptors were correlated with a better survival in our study.
Quantifying the growth of clinical actionability in precision oncology using OncoKB.
Authors: Sarah P. Suehnholz, Ritika Kundra, Subhiksha Nandakumar, Moriah H Nissan, Hongxin Zhang, Calvin Lu, Amanda Dhaneshwar, Nicole Fernandez, Stephanie Carrero, Maria E. Arcila, Marc Ladanyi, Michael F. Berger, Aijazuddin Syed, Angela Rose Brannon, Ross L. Levine, Ahmet Dogan, Alexander E. Drilon, David B. Solit, Nikolaus Schultz, Debyani Chakravarty
Journal: Journal of Clinical Oncology (2023)

1577 Background: OncoKB ( www.oncokb.org ), Memorial Sloan Kettering's (MSK) precision oncology knowledge base, contains curated information about the oncogenic effect and therapeutic implications of somatic alterations in cancer and is the first cancer variant database to be partially recognized by the US-FDA. Individual mutations and structural alterations in OncoKB are assigned a level of evidence based on whether the alteration is a predictive biomarker of response or resistance to a genomically matched standard care or investigational drug in a specific cancer subtype. As of February 2023, OncoKB includes annotations for &gt;6200 alterations in &gt;700 cancer-associated genes, including 50 level 1 or 2 standard care genes (specified in the FDA drug label or professional guidelines) as well as 9 level 3A and 12 level 4 genes (predictive of drug response based on well-powered clinical studies or compelling biological evidence, respectively). OncoKB data is used internally to annotate &gt;15,000 MSK patient sequencing reports annually, and its content is integrated into the cBioPortal for Cancer Genomics. Methods: To quantitate the expansion of the clinical actionability landscape in precision oncology, we annotated the clinical sequencing results of 47,271 solid tumor samples from the AACR Project GENIE cohort (GENIE 11.0 - public) using two versions of OncoKB, the first from March 2017 and the second from November 2022. Results: From 2017 to 2022, we observed a 22.7% increase in the fraction of samples with a standard care biomarker (levels 1 and 2), and a 21.4% decrease in the fraction of samples with a driver alteration that was not clinically actionable. The tumor agnostic approvals of the anti-PD1 antibody pembrolizumab in microsatellite instability high (MSI-H) and tumor mutational burden high (TMB-H) solid tumors resulted in a 11.1%increase of samples with a level 1 biomarker. In sum, of the 38,722 samples across 66 cancer types with limited to no actionability in 2017 (levels 3B, 4 or no level), 21.7% became clinically actionable (levels 1, 2 or 3A) by November 2022. This is an upper bound estimate as it includes samples that may have been eligible for an FDA-approved precision oncology therapy based on cancer subtype alone. Conclusions: Our analysis highlights the significant expansion of precision oncology-based therapeutic options for patients with cancer over the past 5 years, as well as the ongoing unmet need for novel precision oncology approaches designed to address oncogenic but not currently actionable drug targets. [Table: see text]
Influence of chromatin remodeling molecule ARID1A on metastatic heterogeneity in triple negative breast cancer: Binding of YAP.
Authors: Ye Wang, Duancheng Guo, Zhonghua Tao, Xichun Hu
Journal: Journal of Clinical Oncology (2023)

1085 Background: Heterogeneity is the prominent character of TNBC and one predominant cause of treatment failure. As a key nuclear SWI/SNF protein complex subunit, ARID1A plays a critical role in tumor identity determining by manipulating gene expression. The present study aimed to investigate whether and how ARID1A determined the metastatic heterogeneity of triple-negative breast cancer. Methods: This study retrospectively collected and analysed clinical and pathological data from 258 patients diagnosed with triple-negative breast cancer at Fudan University Cancer Hospital from August 2015 to June 2016 to define the prognostic ability of ARID1A.CRISPR/Cas9 or plasmids-mediated ARID1A were used to determine the ARID1A function in regulating the metastatic character in TNBC. Cell morphology, tumor invasion, and metastasis were analyzed in terms of ARID1A status both in vitro and in vivo experiments. The molecular mechanism of ARID1A determining metastasis potential of TNBC was explored by RNA-Seq and nuclear positioning. Results: ARID1A low expression was found to have independent prognostic value for poor OS (43.9 vs 53.6 months, P=0.0001) and RFS (31.0 vs 45.5 months, P=0.0029) in TNBC patients. Both nuclear and cytoplasmic protein analysis and Immunofluorescent localization assay confirm that ARID1A recruits the Hippo pathway effector YAP into nucleus in human triple negative breast cancer cells. Next we designed the YAP truncator plasmid and confirmed by Co-Immunoprecipitation that ARID1A could competitively bind to the WW domain of YAP to form the ARID1A/YAP complex. Furthermore, down-regulation of ARID1A promoted migration and invasion both in human triple negative breast cancer cells and xenograft model through Hippo/YAP signaling axis. Conclusions: Our study provides new insights into the previously unrecognized role of ARID1A in TNBC metastasis, which might provide new therapeutic options for patients with TNBC.
Neoadjuvant stereotactic body radiotherapy plus dalpiciclib and exemestane for hormone receptor-positive, HER2-negative breast cancer.
Authors: Nan Niu, Shuo Cao, Guanglei Chen, Jinqi Xue, Yu Zhang, Yongqing Xu, Jianqiao Yin, Chao Liu, Xiaofan Jiang, Meiyue Tang, Qianshi Xu, Mingxuan Jia, Xu Zhang, Zhenyong Zhang, Huajun Li, Ailin Li, Caigang Liu
Journal: Journal of Clinical Oncology (2023)

e12604 Background: Despite cyclin dependent kinase 4/6 (CDK4/6) inhibitors having revolutionized treatment for advanced hormone receptor (HR)-positive, HER2-negative (HR+/HER2-) breast cancer, it still has limited efficacy in the neoadjuvant setting. Preclinical studies have indicated radiotherapy followed by CDK4/6 inhibitors can enhance antineoplastic effects. Stereotactic body radiotherapy (SBRT) is more effective than conventional fractionation. This MUKDEN 03 pilot study aimed to explore the efficacy and safety of a chemotherapy-free neoadjuvant regimen with SBRT followed by CDK4/6 inhibitors and endocrine therapy in patients with HR+/HER2- breast cancer. Methods: In this single-center, single-arm prospective study, treatment-naïve patients with unilateral invasive, pathologically confirmed HR+/HER2- breast cancer at stage II-III would be enrolled. Eligible patients received neoadjuvant SBRT (24Gy/3f) to breast target lesion followed by dalpiciclib (150mg daily for 3 weeks on and 1 week off) and exemestane (25mg daily) every 4 weeks for 6 cycles. Patients without menopause also received goserelin 3.6 mg every 4 weeks. The primary endpoint was the proportion of patients with residual cancer burden (RCB) score of 0-I. Key secondary endpoints included objective response rate (ORR), pathologic complete response (pCR), and safety. Results: Between November 2021 and August 2022, 12 enrolled patients completed the study treatment and surgery. The median age was 48.5 years (95% confidence interval [CI], 36-56) and half of them were premenopausal women. 5 (41.7%) patients had stage III disease. The results met the primary endpoint as the therapy resulted in RCB 0-I of 16.7% (2/12, 95% CI 3.5%-46.0%) with the ORR of 91.7% (11/12, 95% CI 62.5%-100%). 2 (16.7%, 95% CI 3.5%-46.0%) patients achieved pCR in the breast and axilla (ypT0/is ypN0). 3 (25.0%, 95% CI 8.3%-53.9%) patients reached pCR in the breast (ypT0/is). The most common grade 3 adverse events (AEs) were neutropenia (8 [66.7%]) and leukopenia (3 [25%]). No patient experienced grade 4-5 AE or death. There was no patient with radiation-related dermatitis and skin hyperpigmentation. Conclusions: Neoadjuvant SBRT followed by dalpiciclib and exemestane seems effective and tolerable, which may offer an alternative for patients with HR+/HER2- breast cancer. The results warranted further validation. Clinical trial information: NCT05132790 .
Neoadjuvant tucidinostat combined with chemotherapy for hormone receptor-positive, HER2-negative breast cancer.
Authors: Nan Niu, Jinqi Xue, Fang Qiu, Guanglei Chen, Xi Gu, Guijin He, Shuo Cao, Xiaopeng Yu, Yongqing Xu, Jianqiao Yin, Sijia Han, Ye Han, Meiyue Tang, Yafei Zhao, Ran Zheng, Xinyu Zheng, Hong Xu, Caigang Liu
Journal: Journal of Clinical Oncology (2023)

e12617 Background: Both neoadjuvant chemotherapy and endocrine therapy only result in trivial pathological complete response rates and moderate objective response rate (ORR) in hormone receptor (HR)-positive, HER2-negative breast cancer, more promising alternatives are urgently needed. Tucidinostat is an oral subtype-selective histone deacetylase inhibitor that has shown efficacy and safety when used in combination with exemestane in patients with advanced HR+ breast cancer. This MUKDEN 05 study aimed to assess the efficacy and toxicity of the combination of tucidinostat and EC-T as a neoadjuvant strategy in patients with HR+/HER2-, stage II-III breast cancer. Methods: This study is a multicenter, single-arm, phase II study. Eligible patients received 20 mg tucidinostat orally twice a week (on days 1, 4, 8, and 11), 2 weeks on, 1 week off. The dose and administration schedule of EC-T were as follows: 4 cycles of epirubicin 90 mg/m 2 and cyclophosphamide 600 mg/m 2 every 3 weeks, followed by 4 cycles of docetaxel 100 mg/m 2 every 3 weeks. The primary endpoint was the proportion of residual cancer burden (RCB) 0-I. Key secondary endpoints included pathological complete response (pCR), objective response rate (ORR), and safety. Results: Between May 2022 and August 2022, a total of 35 patients were enrolled. 27 patients were pathologically evaluable. The remaining 8 patients have completed neoadjuvant treatment and wait for operation. The ratio of RCB 0-I was 37% (95% CI, 23.2-53.7%). ORR was 86% (95% CI, 70.6-93.7%). Four (15%; 95% CI, 5.91-32.5%) patients achieved bpCR, and one (4%; 95% CI, 0.67-18.3%) patients achieved tpCR. Most adverse events (AEs) were grade 1 or 2. Grade 3/4 AEs included neutropenia (21.1%), and thrombocytopenia (15.8%). Conclusions: The combination of Tucidinostat and EC-T had an acceptable safety profile and encouraging clinical responses, offering a neoadjuvant treatment option for patients with early HR+/HER2- breast cancer. Further research is required to validate these findings. Clinical trial information: NCT05400993 .
Correlation of breast arterial calcification with overall survival in patients with breast cancer.
Authors: Vidya Sagar Dusi, Suresh VS Attili, Anuradha Vutukuru, Soumya V Peri, Rakesh Sharma
Journal: Journal of Clinical Oncology (2023)

e12501 Background: Calcifications in breast tissue are common and indicate an array of conditions. Based on pattern of calcifications it indicate cancerous/ precancerous changes. Similarly vascular calcifications indicate a systemic vasculopathy. Aim of this study is to correlate Breast Arterial Calcification (BAC) with overall survival/all cause mortality in patients with breast cancer. Methods: It is a retrospective analysis of all breast cancer patients diagnosed across 3 specialty hospitals In the period of 2013-2017 with at least 5 years of follow up. All cause mortality, breast cancer specific mortality were measured. The comparison was made between the patients with no calcifications (Gr I), vascular calcifications (GrII) ductal calcifications (Gr III), and any breast calcification (Gr IV). Results: The baseline characters of all these groups and the treatment received were balanced. The median survival of the Groups were 43.6+22.6 mo vs 28.6+14.2 mo vs38.5+20.2 mo vs41.6+22.3 months (p=&lt;0.02). Presence of vascular calcifications confers shorter overall survival and the main reason being death due to cardiovascular events. The risk is more in presence of co-morbid conditions (&gt;2 have increased risk of 2.8 fold compared to less than 2), which were defined as diabetes, hypertension, dyslipidemia, history of cardiac illness in family, obesity. Those who received Adriamycin based therapy have 1.16 times higher risk than those who did not. Those who smoke are 3.2 times at higher risk than non smokers to have cardiovascular event in presence of breast arterial calcification. Alcohol did not have any impact. Conclusions: BAC is an important marker to predict underlying vasculopathy and risk of coronary cardiac diseases. It confers poor prognosis and reduced overall survival compared to those who do not have it. The challenges to assess CAD risk through CT/angio on community basis is high. Mammograms are being done annually across nations as a routine basis. Risk factors of breast cancer and CAD are common. The cancer detection rates of mammo as &lt;0.2% compared to arterial calcifications, which is almost 12.8%. A simple extra attention towards BAC could help in preventing cardiac related mortality in women both with and without cancer. [Table: see text] [Table: see text]
Is Medicare Advantage associated with more favorable health care access, acute care utilization, and affordability among beneficiaries with cancer?
Authors: Vishal R. Patel, Faraz Jafri, Arjun Gupta, S. M. Qasim Hussaini
Journal: Journal of Clinical Oncology (2023)

1597 Background: The Medicare Advantage (MA) program provides care to nearly half of Medicare beneficiaries, including a rapidly growing population of cancer survivors. Although MA was designed to optimize healthcare access, outcomes, and affordability, it is unknown whether these effects have been achieved in cancer survivors. Methods: We performed a cross-sectional study of Medicare beneficiaries ≥65 years with a self-reported history of cancer in the 2019 National Health Interview Survey. We used multivariable logistic regression to evaluate the association between Medicare program type (MA vs traditional Medicare, TM) and measures of healthcare access, acute care utilization, and affordability. Results: We identified 4,451 beneficiaries with a history of cancer, corresponding to 26.6 million weighted cancer survivors in 2019. Of beneficiaries, 35.8% were enrolled in MA while 64.2% were enrolled in TM. The age, sex, racial and ethnic composition, household income, primary site of cancer, and co-morbidity burden of MA and TM beneficiaries were similar. In adjusted analysis, there were no differences in health care access or acute care utilization between TM and MA beneficiaries. However, survivors enrolled in MA were more likely to worry about (34.3% vs 29.4%; aOR, 1.3 [95% CI, 1.1-1.5]) or have problems paying (13.6% vs 11.1%; aOR, 1.4 [95% CI, 1.1-1.8]) medical bills. Conclusions: MA beneficiaries with a previous cancer diagnosis more often struggle paying medical bills despite similar healthcare access and preventive care as TM. Despite generous benefits and attractive incentives for care coordination and health management, privately run MA plans may not be more cost-effective than TM for cancer survivors. Our study informs ongoing congressional deliberations to re-evaluate the role of MA in promoting equity among beneficiaries.[Table: see text]
Efficacy of tucatinib+trastuzumab+capecitabine (TTC) after trastuzumab-deruxtecan (T-DXd) exposure in Her2-positive metastatic breast cancer: A French multicentre retrospective study.
Authors: Jean-Sebastien Frenel, Jean Zeghondy, Catherine Guerin, Audrey Mailliez, Elsa Volant, Francois Poumeaud, Anne Patsouris, Monica Arnedos, Caroline Bailleux, Julie Cabal, Loick Galland, Alexandre De nonneville, Severine Guiu Lahaye, Florence Dalenc, Barbara Pistilli, Thomas Bachelot, Pierre Martin, Francois Bocquet, Louis Larrouquere, Delphine Loirat
Journal: Journal of Clinical Oncology (2023)

1014 Background: Recent guidelines have positioned T-DXd as a preferred treatment in the second line setting for HER2+ metastatic breast cancer (MBC). TTC is the preferred treatment in third line, however little is known on the efficacy of this combination after T-DXd exposure. Methods: We conducted a retrospective study in 12 French comprehensive cancer centers. All patients with HER2+ MBC treated with TTC after prior exposure to T-DXd were included. The primary end point was progression-free survival (PFS) in the whole population. Secondary end-points included overall survival (OS), PFS in subgroups and objective response rate. Results: Between 08/2020 and 12/2022, 101 patients were included. Median age was 56.4 y.o. (range 30.8 - 84.8). Median number of prior line of treatment for metastatic disease at TTC start was 4 (2 - 15). 82% and 95% of patients had received previous pertuzumab and T-DM1 respectively. The median duration of previous exposure to T-DXd was 8.9 months (1.4 - 31.4) and 82/101 (81%) patients had progressed under T-DXd while 19 had stopped T-DXd for toxicity or other reasons. TTC regimen was given as a 3 rd line or 4 th line for metastatic disease in 37/101 (37%) and beyond for the remaining patients. TTC was the immediate subsequent therapy to T-DXd for 86/101 pts (85%). With a median follow-up of 8.5 m (95%CI [7.7; 9.4]), 68/101pts (67%) have stopped TTC for progressive disease. Median PFS was 4.7 m (95%CI [3.8; 5.6]) and median OS not reached (95%CI [10.6; NA]) in the whole population. Patients treated with TTC as the immediate subsequent therapy to T-DXd, had a median PFS of 5.0 m (95%CI [4.0; 6.0]) and a median OS not reached (95%CI [11.9; NA]). Best response to TTC, evaluated by investigators in the 87/101 RECIST evaluable patients, was progressive disease, stable disease, partial response and complete response in 34%, 34%, 30% and 2% of patients respectively. At TTC initiation, 39 (39%) of patients had known brain metastases. Out of the 62 patients without known brain metastases at the initiation of TTC, 2 had brain metastases documented as a site of progression during TTC. Conclusions: In this large retrospective cohort, TTC shows significant efficacy for patients with HER2+ MBC previously exposed to T-DXd. Data and subgroup analyses will be updated for the meeting.